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ImportanceCorrect diagnosis of ovarian cancer results in better prognosis. Adnexal lesions can be stratified into the Ovarian-Adnexal Reporting and Data System (O-RADS) risk of malignancy categories with either the O-RADS lexicon, proposed by the American College of Radiology, or the International Ovarian Tumor Analysis (IOTA) 2-step strategy.ObjectiveTo investigate the diagnostic performance of the O-RADS lexicon and the IOTA 2-step strategy.Design, Setting, and ParticipantsRetrospective external diagnostic validation study based on interim data of IOTA5, a prospective international multicenter cohort study, in 36 oncology referral centers or other types of centers. A total of 8519 consecutive adult patients presenting with an adnexal mass between January 1, 2012, and March 1, 2015, and treated either with surgery or conservatively were included in this diagnostic study. Twenty-five patients were excluded for withdrawal of consent, 2777 were excluded from 19 centers that did not meet predefined data quality criteria, and 812 were excluded because they were already in follow-up at recruitment. The analysis included 4905 patients with a newly detected adnexal mass in 17 centers that met predefined data quality criteria. Data were analyzed from January 31 to March 1, 2022.ExposuresStratification into O-RADS categories (malignancy risk Main Outcomes and MeasuresObserved prevalence of malignancy in each O-RADS risk category, as well as sensitivity and specificity. The reference standard was the status of the tumor at inclusion, determined by histology or clinical and ultrasonographic follow-up for 1 year. Multiple imputation was used for uncertain outcomes owing to inconclusive follow-up information.ResultsMedian age of the 4905 patients was 48 years (IQR, 36-62 years). Data on race and ethnicity were not collected. A total of 3441 tumors (70%) were benign, 978 (20%) were malignant, and 486 (10%) had uncertain classification. Using the O-RADS lexicon resulted in 1.1% (24 of 2196) observed prevalence of malignancy in O-RADS 2, 4% (34 of 857) in O-RADS 3, 27% (246 of 904) in O-RADS 4, and 78% (732 of 939) in O-RADS 5; the corresponding results for the IOTA 2-step strategy were 0.9% (18 of 1984), 4% (58 of 1304), 30% (206 of 690), and 82% (756 of 927). At the 10% risk threshold (O-RADS 4-5), the O-RADS lexicon had 92% sensitivity (95% CI, 87%-96%) and 80% specificity (95% CI, 74%-85%), and the IOTA 2-step strategy had 91% sensitivity (95% CI, 84%-95%) and 85% specificity (95% CI, 80%-88%).Conclusions and RelevanceThe findings of this external diagnostic validation study suggest that both the O-RADS lexicon and the IOTA 2-step strategy can be used to stratify patients into risk groups. However, the observed malignancy rate in O-RADS 2 was not clearly below 1%.

Objective To estimate the diagnostic value of tumor and immune related proteins in the discrimination between benign and malignant adnexal masses, and between different subgroups of tumors. Methods In this exploratory diagnostic study, 254 patients with an adnexal mass scheduled for surgery were consecutively enrolled at the University Hospitals Leuven (128 benign, 42 borderline, 22 stage I, 55 stage II-IV, and 7 secondary metastatic tumors). The quantification of 33 serum proteins was done preoperatively, using multiplex high throughput immunoassays (Luminex) and electrochemiluminescence immuno-assay (ECLIA). We calculated univariable areas under the Receiver Operating Characteristic Curves (AUCs). To discriminate malignant from benign tumors, multivariable ridge logistic regression with backward elimination was performed, using bootstrapping to validate the resulting AUCs. Results CA125 had the highest univariable AUC to discriminate malignant from benign tumors (0.85, 95% confidence interval 0.79-0.89). Combining CA125 with CA72.4 and HE4 increased the AUC to 0.87. For benign vs borderline tumors, CA125 had the highest univariable AUC (0.74). For borderline vs stage I malignancy, no proteins were promising. For stage I vs II-IV malignancy, CA125, HE4, CA72.4, CA15.3 and LAP had univariable AUCs ≥0.80. Conclusions The results confirm the dominant role of CA125 for identifying malignancy, and suggest that other markers (HE4, CA72.4, CA15.3 and LAP) may help to distinguish between stage I and stage II-IV malignancies. However, further research is needed, also to investigate the added value over clinical and ultrasound predictors of malignancy, focusing on the differentiation between subtypes of malignancy.

Novel treatment strategies are needed to provide a better prognosis for ovarian cancer. For this purpose, the current study was designed to evaluate the effects of different types of particle drug carriers on tumor response and on the tumor immune microenvironment (TME) after intraperitoneal (IP) administration in a murine tumor model. Mice with ID8-fLuc ovarian cancer were injected IP with pegylated liposomes, hydroxyapatite, polystyrene, poly(lactic-co-glycolic acid) (PLGA) and calcium carbonate (CaCO3) microparticles to evaluate the effect of the candidate carriers without drugs. Our results show that several types of microparticle drug carriers caused hyperproliferation of the tumor when injected IP, as reflected in a reduced survival or an accelerated onset of ascites. Alterations of the product formulation of CaCO3 microparticles could result in less hyperproliferation. The hyperproliferation caused by CaCO3 and PLGA was largely driven by a strong innate immune suppression. A combination with chemotherapy was not able to sufficiently counteract the tumor progression caused by the drug carriers. This research points towards the importance of evaluating a drug carrier before using it in a therapeutic setting, since drug carriers themselves can detrimentally influence tumor progression and immune status of the TME. However, it remains to be determined whether the hyperproliferation in this model will be of relevance in other cancer models or in humans. ispartof: PHARMACEUTICS vol:14 issue:4 ispartof: location:Switzerland status: published

Simple Summary The immune system plays an important role in the development and progression of cancer. The current treatments for ovarian cancer (surgery and chemotherapy) create changes in the immune system, but it is not clear how. Nevertheless, if immunotherapy is associated on top of this, then it seems crucial to understand what is changing in the current state of the art. In this study, we measured immune-related proteins in the serum of ovarian cancer patients throughout their treatment. We discovered that carboplatin-paclitaxel as a chemotherapeutic treatment reduces immunosuppression and promotes immunostimulation, meaning that the immune system be-comes less hostile and more in favour of the patient. Therefore, chemotherapy seems to induce a temporary window of opportunity to insert immunotherapy during the current treatment of ovarian cancer patients. In monotherapy, immunotherapy has a poor success rate in ovarian cancer. Upgrading to a successful combinatorial immunotherapy treatment implies knowledge of the immune changes that are induced by chemotherapy and surgery. Methodology: Patients with a new ovarian cancer diagnosis underwent longitudinal blood samples at different time points during primary treatment. Results.: Ninety patients were included in the study (33% primary debulking surgery (PDS) with adjuvant chemotherapy (ACT), 61% neo-adjuvant chemotherapy (NACT) with interval debulking surgery (IDS), and 6% debulking surgery only). Reductions in immunosuppression were observed after NACT, but surgery reverted this effect. The immune-related proteins showed a pronounced decrease in immune stimulation and immunosuppression when primary treatment was completed. NACT with IDS leads to a transient amelioration of the immune microenvironment compared to PDS with ACT. Conclusion: The implementation of immunotherapy in the primary treatment schedule of ovarian cancer cannot be induced blindly. Carboplatin-paclitaxel seems to ameliorate the hostile immune microenvironment in ovarian cancer, which is less pronounced at the end of primary treatment. This prospective study during primary therapy for ovarian cancer that also looks at the evolution of immune-related proteins provides us with an insight into the temporary windows of opportunity in which to introduce immunotherapy during primary treatment.

ObjectiveTo evaluate the performance of diagnostic prediction models for ovarian malignancy in all patients with an ovarian mass managed surgically or conservatively.DesignMulticentre cohort study.Setting36 oncology referral centres (tertiary centres with a specific gynaecological oncology unit) or other types of centre.ParticipantsConsecutive adult patients presenting with an adnexal mass between January 2012 and March 2015 and managed by surgery or follow-up.Main outcome measuresOverall and centre specific discrimination, calibration, and clinical utility of six prediction models for ovarian malignancy (risk of malignancy index (RMI), logistic regression model 2 (LR2), simple rules, simple rules risk model (SRRisk), assessment of different neoplasias in the adnexa (ADNEX) with or without CA125). ADNEX allows the risk of malignancy to be subdivided into risks of a borderline, stage I primary, stage II-IV primary, or secondary metastatic malignancy. The outcome was based on histology if patients underwent surgery, or on results of clinical and ultrasound follow-up at 12 (±2) months. Multiple imputation was used when outcome based on follow-up was uncertain.ResultsThe primary analysis included 17 centres that met strict quality criteria for surgical and follow-up data (5717 of all 8519 patients). 812 patients (14%) had a mass that was already in follow-up at study recruitment, therefore 4905 patients were included in the statistical analysis. The outcome was benign in 3441 (70%) patients and malignant in 978 (20%). Uncertain outcomes (486, 10%) were most often explained by limited follow-up information. The overall area under the receiver operating characteristic curve was highest for ADNEX with CA125 (0.94, 95% confidence interval 0.92 to 0.96), ADNEX without CA125 (0.94, 0.91 to 0.95) and SRRisk (0.94, 0.91 to 0.95), and lowest for RMI (0.89, 0.85 to 0.92). Calibration varied among centres for all models, however the ADNEX models and SRRisk were the best calibrated. Calibration of the estimated risks for the tumour subtypes was good for ADNEX irrespective of whether or not CA125 was included as a predictor. Overall clinical utility (net benefit) was highest for the ADNEX models and SRRisk, and lowest for RMI. For patients who received at least one follow-up scan (n=1958), overall area under the receiver operating characteristic curve ranged from 0.76 (95% confidence interval 0.66 to 0.84) for RMI to 0.89 (0.81 to 0.94) for ADNEX with CA125.ConclusionsOur study found the ADNEX models and SRRisk are the best models to distinguish between benign and malignant masses in all patients presenting with an adnexal mass, including those managed conservatively.Trial registrationClinicalTrials.gov NCT01698632.

The role of the innate immune system in ovarian cancer is gaining importance. The relevance of tumor-associated macrophages (TAM) is insufficiently understood. In this pilot project, comprising the immunofluorescent staining of 30 biopsies taken from 24 patients with ovarian cancer, we evaluated the presence of total TAM (cluster of differentiation (CD) 68 expression), M1 (major histocompatibility complex (MHC) II expression), and M2 (anti-mannose receptor C type 1 (MRC1) expression), and the blood vessel diameter. We observed a high M1/M2 ratio in low-grade ovarian cancer compared to high-grade tumors, more total TAM and M2 in metastatic biopsies, and a further increase in total TAM and M2 at interval debulking, without beneficial effects of bevacizumab. The blood vessel diameter was indicative for M2 tumor infiltration (Spearman correlation coefficient of 0.65). These data mainly reveal an immune beneficial environment in low-grade ovarian cancer in contrast to high-grade serous ovarian cancer, where immune suppression is not altered by neoadjuvant therapy. ispartof: CELLS vol:9 issue:2 ispartof: location:Switzerland status: published

ObjectiveAssess experience of healthcare professionals (HCPs) working with ultrasound in obstetrics and gynaecology during the evolving SARS-CoV-2 pandemic, given the new and unprecedented challenges involving viral exposure, personal protective equipment (PPE) and well-being.DesignProspective cross-sectional survey study.SettingOnline international survey. Single-best, open box and Hospital Anxiety and Depression Scale (HADS) questions.ParticipantsThe survey was sent to 35 509 HCPs in 124 countries and was open from 7 to 21 May 2020. 2237/3237 (69.1%) HCPs from 115 countries who consented to participate completed the survey. 1058 (47.3%) completed the HADS.Primary outcome measuresOverall prevalence of SARS-CoV-2, depression and anxiety among HCPs in relation to country and PPE availability.AnalysesUnivariate analyses were used to investigate associations without generating erroneous causal conclusions.ResultsConfirmed/suspected SARS-CoV-2 prevalence was 13.0%. PPE provision concerns were raised by 74.1% of participants; highest among trainees/resident physicians (83.9%) and among HCPs in Spain (89.7%). Most participants worked in self-perceived high-risk areas with SARS-CoV-2 (67.5%–87.0%), with proportionately more trainees interacting with suspected/confirmed infected patients (57.1% vs 24.2%–40.6%) and sonographers seeing more patients who did not wear a mask (33.3% vs 13.9%–7.9%). The most frequent PPE combination used was gloves and a surgical mask (22.3%). UK and US respondents reported spending less time self-isolating (8.8 days) and lower satisfaction with their national pandemic response (37.0%–43.0%). 19.8% and 8.8% of respondents met the criteria for moderate to severe anxiety and depression, respectively.ConclusionsReported prevalence of SARS-CoV-2 in HCPs is consistent with literature findings. Most respondents used gloves and a surgical mask, with a greater SARS-CoV-2 prevalence compared with those using ‘full’ PPE. HCPs with the least agency (trainees and sonographers) were not only more likely to see high-risk patients but also less likely to be protected. A fifth of respondents reported moderate to severe anxiety.

Dendritic- cells (DCs) have received considerable attention as potential targets for the development of anticancer vaccines. DC-based anticancer vaccination relies on patient-derived DCs pulsed with a source of tumor-associated antigens (TAAs) in the context of standardized maturation-cocktails, followed by their reinfusion. Extensive evidence has confirmed that DC-based vaccines can generate TAA-specific, cytotoxic T cells. Nonetheless, clinical efficacy of DC-based vaccines remains suboptimal, reflecting the widespread immunosuppression within tumors. Thus, clinical interest is being refocused on DC-based vaccines as combinatorial partners for T cell-targeting immunotherapies. Here, we summarize the most recent preclinical/clinical development of anticancer DC vaccination and discuss future perspectives for DC-based vaccines in immuno-oncology. ispartof: ONCOIMMUNOLOGY vol:8 issue:11 ispartof: location:United States status: published

Introduction/Background The KEYNOTE-021 trial showed a beneficial effect of the combination of chemotherapy and immunotherapy in non-small-cell lung cancer, since then multiple trials have studied combination of chemotherapy and immunotherapy. However, not all combinations yield positive results, as we learned from the JAVELIN Ovarian 200 trial. Therefore, we need to gain insight into the effect of chemotherapy on the immune system in vivo. In the current study, we investigated the influence of first-line treatment for ovarian cancer on the immune system. Methodology Tumour biopsies and peripheral blood mononuclear cells were collected prospectively in 43 patients with epithelial ovarian cancer. Samples were taken at diagnosis, after cytoreductive surgery, after three courses of (neo-)adjuvant chemotherapy and at the end of their primary treatment. Immunostimulatory cells (Thelper cells (Th), Tcytotoxic cells (Tc), natural killer cells (NK)) and immunosuppressive cells (regulatory T cells (Treg), mMDSC (monocytic myeloid-derived suppressor cells), gMDSC (granulocytic MDSC)) were measured in blood using fluorescence activated cell sorting. Additionally, we checked for the expression of activation markes and immune checkpoint molecules on immune cells. On tumour biopsies, we performed immunohistochemistry for Tc and Treg. Results First-line treatment led to a significant increase in Tc in circulation (p Conclusion We observed a clear change in the immune phenotype of patients during first-line treatment for epithelial ovarian cancer. Chemotherapy led to an increase in the expression of immune checkpoint markers on Th, Tc and Treg in blood. Disclosure TB has reported research grant from Amgen, travel expenses from Amgen and Roche as well as advisory board membership for Tesaro. IV has performed contracted research for Oncoinvent AS and Genmab, received research grants from Amgen, Roche, Stichting tegen Kanker, received travel expenses from Takeda Oncology, Pharma Mar, Genmab, Roche, Astrazeneca, Tesaro, Clovis, Immunogen and is a advisory board member for Advaxis, Inc., Eisai Inc., MSD Belgium, Roche NV, Genmab, F. Hoffmann-La Roche Ltd, Pharmamar, Millennium Pharmaceuticals, Clovis Oncology Inc., AstraZeneca NV, Tesaro, Oncoinvent AS, Immunogen Inc and Sotio. CL, JC, GT, AVH, TV, A-SVR, AdB, DT and AC have no disclosures concerning this abstract.